The present invention provides a prodrug of propofol and crystalline forms thereof, methods of making the propofol prodrug and crystalline forms thereof, pharmaceutical compositions of the propofol prodrug and crystalline forms thereof, methods of using the propofol prodrug and crystalline forms thereof and pharmaceutical compositions thereof to treat or prevent diseases or disorders such as headache pain, post-chemotherapy or post-operative surgery nausea and vomiting neurodegenerative disorders, and mood disorders.
Propofol (2,6-diisopropylphenol), (1), is a low molecular weight phenol that is widely used as an intravenous sedative-hypnotic agent in the induction and maintenance of anesthesia and/or sedation in mammals. The advantages of propofol as an anesthetic include rapid onset of anesthesia, rapid clearance, and minimal side effects (Langley et al., Drugs 1988, 35, 334-372, which is incorporated by reference herein in its entirety). Propofol may mediate hypnotic effects through interaction with the GABAA receptor complex, a hetero-oligomeric ligand-gated chloride ion channel (Peduto et al., Anesthesiology 1991, 75, 1000-1009, which is incorporated by reference herein in its entirety).

Propofol is rapidly metabolized in mammals with the drug being eliminated predominantly as glucuronidated and sulfated conjugates of propofol and 4-hydroxypropofol (Langley et al., Drugs 1988, 35, 334-372). Propofol clearance exceeds liver blood flow, which indicates that extrahepatic tissues contribute to the overall metabolism of the drug. Human intestinal mucosa glucuronidates propofol in vitro and oral dosing studies in rats indicate that approximately 90% of the administered drug undergoes first pass metabolism, with extraction by the intestinal mucosa accounting for the bulk of this presystemic elimination (Raoof et al., Pharm. Res. 1996, 13, 891-895, which is incorporated by reference herein in its entirety). Because of its extensive first-pass metabolism, propofol is administered by injection or intravenous infusion and oral administration has not been considered therapeutically effective.
Propofol has a broad range of biological and medical applications, which are evident at sub-anesthetic doses and include treatment and/or prevention of intractable migraine headache pain (Krusz et al., Headache 2000, 40, 224-230; Krusz, International Publication No. WO 00/54588, each of which is incorporated by reference herein in its entirety). Propofol, when used to maintain anesthesia, causes a lower incidence of post-operative nausea and vomiting (PONV) when compared to common inhalation anesthetic agents and numerous controlled clinical studies support the anti-emetic activity of propofol (Tramer et al., Br. J. Anaesth. 1997, 78, 247-255; Brooker et al., Anaesth. Intensive Care 1998, 26, 625-629; Gan et al., Anesthesiology 1997, 87, 779-784, each of which is incorporated by reference herein in its entirety). Propofol has also been shown to have anti-emetic activity when used in conjunction with chemotherapeutic compounds (Phelps et al., Ann. Pharmacother. 1996, 30, 290-292; Borgeat et al., Oncology 1993, 50, 456-459; Borgeat et al., Can. J. Anaesth. 1994, 41, 1117-1119; Tomioka et al., Anesth. Analg. 1999, 89, 798-799, each of which is incorporated by reference herein in its entirety). Nausea, retching and/or vomiting induced by a variety of chemotherapeutic agents (e.g., cisplatin, cyclophosphamide, 5-fluorouracil, methotrexate, anthracycline drugs, etc.) has been controlled by low-dose propofol infusion in patients refractory to prophylaxis with conventional anti-emetic drugs (e.g., serotonin antagonists and corticosteroids).
Propofol has also been used to treat patients with refractory status epilepticus (Brown et al., Pharmacother. 1998, 32, 1053-1059; Kuisma et al., Epilepsia 1995, 36, 1241-1243; Walder et al., Neurology 2002, 58, 1327-1332; Sutherland et al., Anaesth. Intensive Care 1994, 22, 733-737, each of which is incorporated by reference herein in its entirety). Further, the anticonvulsant effects of propofol have also been demonstrated in rat efficacy models at sub-anesthetic doses (Holtkamp et al., Ann. Neurol. 2001, 49, 260-263; Hasan et al., Pharmacol. Toxicol. 1994, 74, 50-53, each of which is incorporated by reference herein in its entirety).
Propofol has also been used as an antioxidant (Murphy et al., Br. J. Anaesth. 1992, 68, 613-618; Sagara et al., J. Neurochem. 1999, 73, 2524-2530; Young et al., Eur. J. Anaesthesiol. 1997, 14, 320-326; Wang et al., Eur. J. Pharmacol. 2002, 452, 303-308, each of which is incorporated by reference herein in its entirety). Propofol, at doses typically used for surgical anesthesia, has observable antioxidant effects in humans (De la Cruz et al., Anesth. Analg. 1999, 89, 1050-1055, which is incorporated by reference herein in its entirety). Pathogenesis or subsequent damage pathways in various neurodegenerative diseases involve reactive oxygen species and accordingly may be treated or prevented with antioxidants (Simonian et al., Pharmacol. Toxicol. 1996, 36, 83-106, which is incorporated by reference herein in its entirety). Examples of specific neurodegenerative diseases, which may be treated or prevented with anti-oxidants include, but are not limited to, Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Pick's disease, inflammatory diseases, and diseases caused by inflammatory mediators such as tumor necrosis factor (TNF) and IL-1.
A significant problem with the formulation and use of propofol is poor water solubility. Accordingly, propofol must be specially formulated in aqueous media using solubilizers or emulsifiers (Briggs et al., Anaesthesia 1982, 37, 1099-1101). For example, in a current commercial product (Diprivan®, Astra-Zeneca) an oil-in-water emulsion (the emulsifier is the lecithin mixture Intralipid®), is used to formulate propofol (Picard et al., Anesth. Analg. 2000, 90, 963-969). Unfortunately, the oil-in-water emulsion formulation causes discomfort and pain at the site of injection.
One potential solution to the poor water solubility of propofol, which avoids the use of additives, solubilizers or emulsifiers and the attendant injection site pain, is a water-soluble, stable propofol prodrug that is converted to propofol in vivo. (Hendler et al., International Publication No. WO 99/58555; Morimoto et al., International Publication No. WO 00/48572; Hendler et al., U.S. Pat. No. 6,254,853; Stella et al., United States Patent Application No. US2001/0025035; Hendler, U.S. Pat. No. 6,362,234; Hendler, International Publication No. WO 02/13810; Sagara et al., J. Neurochem. 1999, 73, 2524-2530; Banaszczyk et al., Anesth. Analg. 2002, 95, 1285-1292; Trapani et al., Int. J. Pharm. 1998, 175, 195-204; Trapani et al., J. Med. Chem. 1998, 41, 1846-1854; Anderson et al., J. Med. Chem. 2001, 44, 3582-3591; and Pop et al., Med. Chem. Res. 1992, 2, 16-21). Propofol prodrugs that are sufficiently labile under physiological conditions to provide therapeutically effective concentrations of propofol, particularly when the prodrug is orally administered, have been described (Gallop et al., U.S. patent application Ser. No. 10/766,990, which is incorporated by reference herein in its entirety).
In general, crystalline forms of drugs are preferred over amorphous forms of drugs, in part, because of their superior stability. For example, in many situations, an amorphous drug converts to a crystalline drug form upon storage. Because amorphous and crystalline forms of a drug typically have differing physical/chemical properties, potencies and/or bioavailabilities, such interconversion is undesirable for safety reasons in pharmaceutical administration. A key characteristic of any crystalline drug substance is the polymorphic behavior of such a material. Polymorphs are crystals of the same molecule, which have different physical properties because the crystal lattice contains a different arrangement of molecules. The different physical properties exhibited by polymorphs affect important pharmaceutical parameters such as storage, stability, compressibility, density (important in formulation and product manufacturing) and dissolution rates (important in determining bioavailability). Stability differences may result from changes in chemical reactivity (e.g., differential hydrolysis or oxidation, such that a dosage form discolors more rapidly when comprised of one polymorph than when comprised of another polymorph), mechanical changes (e.g., tablets crumble on storage as a kinetically favored crystalline form converts to thermodynamically more stable crystalline form) or both (e.g., tablets of one polymorph are more susceptible to breakdown at high humidity). Solubility differences between polymorphs may, in extreme situations, result in transitions to crystalline forms that lack potency or are toxic. In addition, the physical properties of the crystalline form may be important in pharmaceutical processing. For example, a particular crystalline form may form solvates more readily or may be more difficult to filter and wash free of impurities than other forms (i.e., particle shape and size distribution might be different between one crystalline form relative to other forms).
room Agencies such as the United States Food and Drug Administration can require that the polymorphic content of a drug product be monitored and controlled if the most thermodynamically stable polymorphic form of the drug is not used and/or different polymorphic forms of the drug can affect the quality, safety, and/or efficacy of the drug product. Thus medical and commercial reasons favor synthesizing and marketing solid drugs as the thermodynamically stable polymorph, substantially free of kinetically favored polymorphs.
Accordingly, a need exists for a new propofol prodrug and crystalline forms thereof. The crystalline forms thereof can exhibit have superior physicochemical properties that may be used advantageously in pharmaceutical processing and pharmaceutical compositions. These prodrug and crystalline forms thereof should be sufficiently labile under physiological conditions to provide therapeutically effective concentrations of propofol, particularly when the prodrug is orally administered.
The propofol prodrug 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or pharmaceutically acceptable salts, or solvates thereof and crystalline forms thereof are provided that satisfies these and other needs. Further provided are pharmaceutical compositions of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or pharmaceutically acceptable salts, or solvates thereof and crystalline forms thereof, methods of using crystalline forms of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or pharmaceutically acceptable salts, or solvates thereof (including pharmaceutical compositions thereof) to treat or prevent various diseases, and methods of making crystalline forms of 2-amino-3-(2,6-diisopropylphenoxy-carbonyloxy)-propanoic acid or pharmaceutically acceptable salts, or solvates thereof.
In one aspect, the propofol prodrug 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing is provided.
In another aspect, crystalline forms of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid hydrochloride are provided. In some embodiments, a crystalline form of the hydrochloride salt of (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid having characteristic peaks (2θ) at 5.1°±0.2°, 9.7°±0.2°, 11.0°±0.2°, 14.1°±0.2°, 15.1°±0.2°, 15.8°±0.2°, 17.9°±0.2°, 18.5°±0.2°, 19.4°±0.2°, 20.1°±0.2°, 21.3°±0.2°, 21.7°±0.2°, 22.5°±0.2°, 23.5°±0.2°, 24.4°±0.2°, 25.1°±0.2°, 26.8°±0.2°, 27.3°±0.2°, 27.8°±0.2°, 29.2°±0.2°, 29.6°±0.2°, 30.4°±0.2°, and 33.4°±0.2° in an X-ray powder diffraction pattern, as substantially shown in FIG. 1 is provided.
In another aspect, crystalline forms of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate are provided. In some embodiments, a crystalline form of the mesylate salt of (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid having characteristic peaks (2θ) at 4.2°±0.1°, 11.7°±0.1°, 12.1°±0.1°, 12.6°±0.1°, 16.8°±0.1°, 18.4°±0.2°, 21.0°±0.1°, 22.3°±0.1°, 22.8°±0.2°, 24.9°±0.2°, 25.3°±0.1°, 26.7°±0.2°, and 29.6°±0.1° in an X-ray powder diffraction pattern, as substantially shown in FIG. 2 is provided.
In still another aspect, pharmaceutical compositions of the propofol prodrug 2-amino-3-(2,6-diisopropylphenoxy-carbonyloxy)-propanoic acid or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing is provided or a crystalline form of any of the foregoing are provided. The pharmaceutical compositions comprise a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid or a pharmaceutically acceptable salt thereof, or a solvate of any of the foregoing or a crystalline form of any of the foregoing and a pharmaceutically acceptable vehicle. In certain embodiments, a pharmaceutical composition comprising crystalline (S)-2-amino-3-(2,6-diisopropylphenoxy-carbonyloxy)-propanoic acid hydrochloride having characteristic absorption peaks, supra, and a pharmaceutically acceptable vehicle is provided. In certain embodiments, a pharmaceutical composition comprising crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate having characteristic absorption peaks, supra, and a pharmaceutically acceptable vehicle is provided.
In still another aspect, methods for treating or preventing various diseases or disorders are provided. The methods are useful for treating or preventing diseases or disorders including, but not limited to, headache pain such as migraine, post-chemotherapy or post-operative surgery nausea and vomiting, mood disorders such as depression, and neurodegenerative disorders (e.g., epilepsy, Friedrich's disease, Parkinson's disease, Alzheimer's disease, Huntington's disease, amyotrophic lateral sclerosis (ALS), multiple sclerosis (MS), Pick's disease, etc.). In certain embodiments methods involve administering to a patient in need of such treatment or prevention a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid hydrochloride or crystalline forms thereof, or pharmaceutical compositions thereof. In some embodiments, crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid hydrochloride or pharmaceutical compositions thereof with the characteristic absorption peaks, supra, is administered to the patient in need of such treatment. In certain embodiments the methods involve administering to a patient in need of such treatment or prevention a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate or crystalline forms thereof, or pharmaceutical compositions thereof. In some embodiments, crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate or pharmaceutical compositions thereof with the characteristic absorption peaks, supra, is administered to the patient in need of such treatment.
In still another aspect, methods for inducing and/or maintaining anesthesia or sedation in a mammal are provided. In certain embodiments, the methods involve administering to a patient in need of such anesthesia or sedation induction and/or maintenance a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxy-carbonyloxy)-propanoic acid hydrochloride or crystalline forms thereof, or pharmaceutical compositions thereof. In certain embodiments, crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid hydrochloride with characteristic absorption peaks, supra, is administered to the patient in need of such treatment. In certain embodiments, the methods involve administering to a patient in need of such anesthesia or sedation induction and/or maintenance a therapeutically effective amount of 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate or crystalline forms thereof, or pharmaceutical compositions thereof. In some embodiments, crystalline (S)-2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid mesylate with characteristic absorption peaks, supra, is administered to the patient in need of such treatment.
In still another aspect, methods for making 2-amino-3-(2,6-diisopropylphenoxycarbonyloxy)-propanoic acid and/or crystalline forms thereof are provided.
These and other features of the present disclosure are set forth herein.